• Squatting forces blood from the legs back to the heart: Increases preload Source
• MVP causes and mid systolic click and late systolic murmur.

old test was urinary 5-hydroxyindoleacetic acid.

Hormone secreting cells in the pituitary are acidophils and basophils. Acidophils are somatotrophs and lactotrophs.

• Screening : First line test is IGF 1.
• OGTT suppression test: Diagnostic, done when IGF-1 is elevated OR when IGF-1 is equivocal with suggestive clinical features.

IGF has the longer half life; therefore it's used as a screening test for acromegaly. GH has a short half life and levels fluctuate throughout the day so it's not the first test in screening.

• Hypoglycaemia and starvation, high protein diet (increased cirulating amino acids) and stress.

• Positive nitrogen and phosphorous balance.
• Metabolic rate is increased, serum cholesterol is reduced.
• Na and K+ retention. (not adrenal gland mediated)
• Rise in plasma phosphoros, positive nitrogen balance (but lower serum amino acid levels)
• Decrease in blood urea nitrogen.
• Apparently, there's an increase in urine ammonia excretions despite a positive nitrogen balance. Source and Source

• Doxycyline is the DOC for ambulatory patients.
• Penicilin or ceftriaxone for severe disease.
• So far, antibiotic resistance has not been reported as a problem. (so ABST is not needed).
• Pulsed steroid therapy can be given for severe disease (esp. pulmonary involvement)
• The role of plasma exchange is supported by anecdotal evidence and but it seems to work.

### Summary of enzymes involved

• AOSD is a diagnosis of exclusion;

• When to suspect: Any adult with daily or twice daily fever spikes with evanescent, salmon pink, non pruritic rash (which disappears with settling fever)

• Also, arthritis, #lymphadenopathy , sore throat and #splenomegaly

• Rash disappears during afebrile periods; present on trunk and extremities. Non pruritic.

• CRP markedly elevated.

• Investigations: neutrophil leukocytosis, thrombocytosis, anaemia, elevated transaminases; very high ferritin
  | Still's | Very high ferritin; not seen in other diseases |
  | SLE | ANA is positive; ANA not positive in AOSD |

• Characteristic feature: Fusion of wrist joints;

• Rash mostly affects chest and thighs.

• Pancytopaenia with bleeding manifestations: purpura, easy bruising, mucosal bleeds. (low fibrinogen levels seen)

• also ⬆liver enzymes, ⬆Triglycerdies ⬆LDH and ⬇Na levels,

• Management: High dose IV corticosteroids or High dose IVIG +/- cylcosporine / cyclophosphamide.

1. Erythrocytosis (Differentiating factor from other haematologic neoplastic diseases is increased red cell mass)

• JAK2 mutation +ve (in almost all) - usually a point mutation.
• Increased LDH (?increased turnover)
• Blood picture: Excess of NCNC red cells but in post-polycythemic myelofibrosis stage => leukoerythroblastic blood picture #leukoerythroblastic blood picture.

Caused by rickettsia : obligate intracellular gram -ve bacteria with varying morphology

Note: Ticks Vs. fleas : ticks are much larger and have eight legs. Ticks aren't involved in typhus.
Chiggers aren't insects. They are mites.

• Rash - a small, painless, gradually enlarging papule, which leads to an area of central necrosis and is followed by eschar formation.
• A more widespread macular / maculopapular rash may also be seen. Source in about 50% of patients.
  • Pneumonitis or encephalitis, Central nervous system (CNS), pulmonary, or cardiac involvement, Rarely, acute renal failure, shock, and disseminated intravascular coagulation (DIC) can occur!
• may have #splenomegaly, and #hepatomegaly. Source
  Endemic typhus serves as the prototype for pathogenesis:
  The body louse carries ricketsia in it's gut. Tick bite causes itching and during itching tick faeces are inoculated into the the bite site.

• Ricketsia enter the blood stream and infect the endothelium causing systemic vasculitis.
• May cause decreased perfusion to organs and necrosis of extremities (Nose,ear lobes, genitalia.
• Vasculitis -> loss of intravascular colloid -> ?cause of hypoalbuminaemia
• Electrolyte loss is common.

Epidemic typhus causes the most severe clinical presentation -> severe epidemic typhus may develop gangrene, leading to a loss of digits, limbs, or other appendage.

• Weil - Felix test - not sensitive or specific; is a heterophile antibody test based on shared antigens between ricketsia and proteus. Should be carried out 5 - 7 days after onset of fever. slideshare presentation
• An infection is confirmed by a 4-fold increase in antibody titers between acute and convalescent serum specimens - (serologic testing not useful acutely). IgM appears in 1 week, IgG appears in 2 weeks.

- Thrombosis: **renal vein thrombosis is a recognised complication of nephrotic syndrome** (occuring in 33%)

[!INFO] Presentation of renal vein thrombosis:

• Acute: flank pain, gross / microscopic haematuria, enlarged kidney on USS, elevated LDH with normal liver enzymes.
• Chronic: Asymptomatic; Usually incidentally found on investigation of pulmonary embolus.

2. 📑IgA📑It causes recurring episodes of microscopic or gross haematuria lasting a few days. Usually recurs every few months after the onset.
3. Begins with haematuria 1-2 days after non specific upper respiratory tract infection.

[!INFO] 95% of TTP is immune mediated
Only a tiny percetage is hereditary.

Mnemonic; Transfer

1. Thrombocytopaenia
2. schistocytic anaemia
3. renal impairment

6. immunosuppresion
7. neurology - uraemai -> CNS depression,  ⬇ seizure threshold, asterexis, tremmor, myoglonus, axiety + depression, impaired cognition
    1. Autonomic dysfunction : increased cirulating catecholamines -> alpha receptor down regulation. 
    2. Peripheral - median nerve compression due to Beta 2 microglobulin amyloidosis. 
    3. Advaned uraemia -> symmetrical polyneuropathy.

Immunosuppression in CKD

Clinical implications

• Once infected with Mycobacterium tuberculosis, dialy­sis patients have a 20-fold increased risk of developing active disease.
• Half of patients have some degree of anergy to the tuberculin skin test.Source

Pathogenesis

Source

• CKS patients are characterized by 'complex impairment of the immune system'.
• There is
  • low grade chronic inflammation -> leads to marked increased in cardiovascular mortality.
  • Inability to mount immune responses -> increased risk of malignancy and infection.
• Pathogenesis: Not completely known but uraemic toxins probably have some role.

- They are peptides *similar in structure to insulin* and are **produced in the liver.**
- **IGF-I peaks in puberty** and it's main role is skeletal and cartilage growth. It is stimulated by GH.

However, crystals can precipitate and cause nephropathy. Prevented by adequate hydration.
Neurotoxicity is rare bu[[]]t can cause delirium, tremors, hallucinations and if severe delerium and coma.
Pan-systolic - ventricle leaks to a lower pressure chamber or vessels - MR, TR, VSD

Types of diastolic murmurs

• AR - decrescendo, early diastolic murmur heard best at left lower sternal border.

Mid diastolic

• Austin flint murmur occurs in severe AR and is a late diastolic or presystolic murmur.
  • "low pitched presystolic blubbering"
• Carey coombs - occurs during acute rheumatic carditis due to mitral valve thickening.
  • low pitched (bell), with the patient in the left lateral decubitus position at end expiration.

Mid diastolic - MS, TS,

• Acute, asymmetrical, lower limb oligoarthritis days to weeks after infection such as dysentery or some sexually acquired infections.
• Classic triad: Non-infectious urethritis, Arthritis, Conjunctivitis
• Mnemonic: AUC (Area under the curve)
• Triggers: dysentery due to salmonella, shigella, or sexually transmitted chlamydia or ureaplasma.
• Enthesitis causing plantar fascitis or achilles tendon enthesitis can occur.
• Sacroilitis and spondylitis can also develop.
• Sterile conjunctivitis
• Acute anterior uveitis
  • 
• Dactylitis
• Many GU symptoms ?due to urethritis including clear discharge.
• Majority of patients recover in 6 months but 30% develop chronic symtpoms.
• Management is symptomatic. (NSAIDS, corticosteroids, DMARDS like sulfasalazine and infliximab is NSAIDS don't work or a contraindicated)
• Usually settles with treatment of the infection.

• New name is DRESS. "Drug reaction with eosinophilia and systemic symptoms."
• A severe adverse drug reaction
• Characterized by extensive skin rash and visceral organ involvement. + lymphadenopathy + eosinophilia + atypical lymphocytosis.
• Occurs between 2 - 8 weeks after starting the drug. (not immediately)
• Can occur with many drugs, including antiepileptics.
• Features:
  • Fever
  • Rash - maculopapular. Mucosal involvement can occur but much less than SJS.
  • Facial oedema
  • Lymphadenopathy
  • Any other organ involvement
    • Commonest is liver
    • AKI, Heart, pulmonary

Enzyme pathways

CYP2D6 and CYP3A4 are hepatic drug metabolism pathways / enzymes

First pass metabolism

#2019BSQ-OCT/Q14

"The first pass effect is a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation." Basically 👇🏽

First pass effect - drug gets metabolized at a non target organ so that affective dose at the target organ is reduced. Commonest site for this to happen is the liver.

P-glycoproteins in the gut can cause efflux of drugs, reducing absorption. Another example of first pass effect.

First pass metabolism varies between people.
First pass effect is significant only if the liver metabolizes the drug rapidly.
So even though the following are completely eleminated by the liver, since the rate of elimination is low, first pass effect is not significant
e.g. for diazepam, phenytoin, theophylline, warfarin.

In cirrhosis, first pass metabolism is reduced because of

1. Reduced hepatic function
2. Blood bypassing the liver due to portosystemic shunting

Drugs with high first pass metabolism:

Effects of having high first pass metabolism

• drug concentration peaks can occur much earlier than they would in a parenteral dose
• oral dose must be much higher
• drugs subject to the first-pass effect are prone to more drug interactions

📑More drugs with high FP metabolism:

1. buspirone,
2. atorvastatin,
3. cyclosporine,
4. felodipine,
5. 📑midazolam,
6. 📑nifedipine,
7. 📑propranolol
8. alprenolol,
9. 5-fluorouracil,
10. 📑 morphine,
11. pentazocine, and
12. mercaptopurine
    

First pass metabolism occurs in the 📑gut for 📑 benzylpenicillin (penicillin G) and insulin and
in the liver for propranolol, lignocaine, chloromethiasole and GTN.

Phase 1 and phase 2 metabolism

Source

Phase 1: Oxidation, reduction and hydrolysis reactions - make the drug more polar and water soluble. Fa
Geriatric patients have reduced phase 1 reaction rates.
Phase 1 is catalyzed by the membrane-bound cytochrome P450.

Phase 2: glucuronidation, acetylation and sulfation - make a drug even more soluble by conjugation with another group.
Acetylation is one example. Patients can be slow or fast acetylators. [[Tuberculosis#Isoniazid]]

Phase 2 reactions occur on a metabolite formed by a phase I reaction that is still not adequately hydrophilic.
Phase II reactions result in the formation of readily excreted, less active,nontoxic substances.
They occur within hepatocytes cytoplasm.

Therapeutic index

$$ Therapeutic; index = \frac{LD_50}{ED_50} $$
LD50 = median lethal dose
ED50 = median effective dose


Digoxin

#2020SBR-NOV/Q03
Cardiac glycoside - Found in [[Plant toxins|Kaneru]]
Classified as Other in Vaughan Williams anriarrhythmic classification.
[[VaughanWilliamsClassificationAntiarrhythmics.png]]

Cardiac glycosides reversibly inhibit the sodium-potassium-ATPase, causing an increase in intracellular sodium and a decrease in intracellular potassium.

Indications and mechanism of action
Overall effects : increased contractile velocity (increased contractility) and decreased heart rate.

1. Heart failure - inhibition of Na/K ATPase -> increased intra-myocyte sodium -> decreased Na calcium exchange -> reduced secretion of calcium -> increased intracellular calcium -> contractility increased.

• However, elevated intracellular calcium also increases risk of arrhythmias.

In patients with HF, digoxin also inhibits sympathetic outflow and augments parasympathetic tone.

• Increased parasympathetic tone to the SA node and AV node -> (via 📑 hypersensitization of carotid sinus baroreceptors, central stimulation, increased vagal output, and possible potentiation of the effect of acetylcholine on the sinoatrial [SA] node) -> 📑slowing the firing of the SA node and prolonging conduction at the atrioventricular (AV) node.
• supratherapeutic doses can cause sinus brady, AV block, arrhythmias

Antiarrhythmic - slows conduction through the AV node, increases vagal tone. This property is used to slow the ventricular rate in patients with persistent AF.

📑Avoid in acute coronary syndrome

[!INFO] Benign effects on the ECG:
Source
#2020GM-JUL/Q02
These effects occur at therapeutic doses

• Downsloping ST depression - 'salvador dali' or 'reverse tick' appearance.
• Biphasic T waves.(negative deflection followed by positive) (or even flattened of inverted T waves)
• The preceding two changes are used by decreased in the atrial and ventricular refractory periods and alterations in ventricular repolorization.
• Shortening of QT interval
• Mild prolongation of the PR interval due to increased vagal tone to the AV node.
  

Is a water soluble drug (renally excreted) ?but has large volume of distribution - Distributed within skeletal and cardiac muscle. Patients with low muscle mass (elderly) or renal failure will need loading dose adjustment.
Drug has a large Vd. so it's makes sense that it exerts it's effects on muscle.

Digoxin toxicity

Factors predisposing to toxicity

• Has a narrow therapeutic window
• Especially hypokalemia or hypomagnesemia can potentiate toxicity.
• Hypercalcemia can increase risk of toxicity. Hypocalcemia can nullify digoxin effects. -> maintain normal electrolyte levels.
• Renal dysfunction increases digoxin levels and often precipitate toxicity!
• Drug interactions
  • Amiodarone and verapamil displace digoxin from tissue binding sites and reduce renal excretion

Acute toxicity

Acute toxicity is uncommon: Effects are

• Hyperkalemia (inhibition of Na/K ATPase),
• confusion and weakness is COMMON
• hypomagnesemia,
• hypoxia will predispose to exagerrated action of digoxin. - Correct before administration.

Chronic toxicity

• Hypokalemia
• Symptoms - GI: N/V/D Dizziness, CNS may be prominent : Confusion, Delirium
• Bradycardia
• Supraventricular tachycardias (?due to increase automaticity) with or without heart block
• Ventriular tachycardia
• Ventricular ectopics (premature ventricular complexes)
• Hyperkalemia (inhibition of Na/K Pump)
• 📑Side effect: Gynaecomastia

[!WARNING] Common effects of digoxin toxicity on the ECG
Other common dysrhythmias associated with digoxin toxicity include:

• Frequent PVCs (the most common abnormality), including ventricular bigeminy and trigeminy
• Sinus bradycardia
• Slow Atrial Fibrillation
• Any type of AV block (1st degree, 2nd degree & 3rd degree)
• Regularised AF = AF with complete heart block and a junctional or ventricular escape rhythm
• Ventricular tachycardia, including polymorphic and bidirectional VT
• Source

Management

• Atropine for bradycardia
• Digoxin specific antibody fragments (Digoxin Fab) - if severe bradycardia and hypotension OR severe hyperkalemia (Serum sickness is a rare but life threatening side effect of antibody fragment treatment)
• Apparently magnesium chloride can be used in digoxin toxicity. (Rang&Dale)

Psychiatric drugs

See [[Psychiatric drugs]]

Anti-epileptic drugs

Source
Focal seizure = previously called partial seizures.
Focal onset aware seizure = simple partial seizure = person doesn't lose awareness of surroundings.

Types of antiepileptic medications

#2020BSQ-JUL/Q22

• Carbamazepine, phenobarbital and phenytoin are "narrow spectrum" -> used mainly for focal onset seizures.

  • Carbamazepine is effective for partial seizures

• Clobazam, lamtotrigine, levetiracetam, topiramate, valproate are "broad spectrum" -> used for both focal and generalized seizures.

  • Valproate, lamotrigine and levetiracetam are newer antiepileptic drugs so they have broader spectrum than the older ones. These 3 are active against both primary and secondary generalized epilepsy.
  • Mnemonic: VLL
  • Valproate is good for almost everything, including absence, myotonic, myoclonic, partial, secondary generalized.
  • Same with lamotrigine.

• Ethosuximide -> used for absence seizures.

  • Does not work for partial seizures.

• Levetiracetam: Drug of choice for partial and / or secondary generalized seizures. Non sedating.

• Lamotrigine is also a first line drug for partial and generalized epilepsy. Non sedating.

Source + Bennet & Brown.

Antiepileptic drugs which may worsen seizures

• Carbamazepine -> can worsen absence, myoclonic and atonic seizures, and primary generalized seizures.
• Phenytoin -> can worsen absence, myoclonic seizures.
• Lamotrigine -> can worsen myoclonic seizures

These drugs, (among others) work by blocking sodium channels.
They show 'use dependence' whereby more frequently depolarizing neurons are affected more.

Lamotrigine

Is a substrate for inducible hepatic enzymes; dose must be increasedin pregnancy!!

Benzodiazepiens

are used for acute management of seizure. Not for seizure prophylaxis.
However, clonazepam is used to achieve rapid control of epilepsy. (eg. When a patient with frequent seizures presents for the first time).

Valproate

Special because it's useful for myoclonic, tonic clonic and absence seizures.
Low toxicity; Non sedative.
Multiple mechanisms of action:

• Inhibition of Na channels.
• Increases GABA levels.
• Inhibits T type calcium channels
  Side effects:
• Hair curling / thinning (alopecia)
• Hepatotoxicity
• Very Potent teratogen (more than other AEDs)
  

Phenytoin metabolism and toxicity

[!TIP] Overview
Effective anti epileptic but with unpredictable pharmacology and significant toxic effects.

[!SUMMARY] Phenytoin
Phenytoin is a second line antiepileptic (now used mainly in ED settings) with narrow therapeutic window.
It has multiple side effects.

• Acute toxicity can produce motor symptoms.
• Low protein states, uraemia, and liver dysfunction predispose to toxicity.
• Gum swelling, hypertrichosis and idiosyncratic TEN are important side effects

Mechanism:
Phenytoin binds to and inhibits voltage-dependent sodium channels, which are found on both neuronal and cardiac tissue.
Cardiac effect: shortens actions potentials and prolongs refractory period between them.`

Pharmacokinetics

#2020BSQ-NOV/Q15

• 0 order / zero order kinetics at therapeutic concentrations (saturation kinetics)
  • plasma half life increases with dose!
  • 1st order kinetics at lower concentrations
• Narrow therapeutic index.
• Phenytoin is 90% protein bound. (Warfarin is also highly protein bound).
  • Uraemia-> uraemic toxins displace phenytoin from Albumin -> higher plasma concentration of phenytoin --> toxicity.
  • Also, low protein states (pregnancy, nephrotic syndrome, malnutrition) -> increase free phenytoin concentration.

pharmacodynamics

Enzyme inducer.

Interactions

Valproate displaces phenytoin from bound proteins -> increased risk of toxicity.
Ethanol / Phenobarbital

• -> initially competitively inhibit phenytoin metabolism -> increase phenytoin concentration.
• -> Later, induce phenytoin metabolising enzymes -> decrease phenytoin concentration.

Clinical

• Oral and IV forms are available.
• Used for GTCs.
• Complex partial seizures
• Status epilepticus

Phenytoin toxicity

Symptoms : N/V, headache,
motor effects: nystagmus, tremor, cerebellar ataxia.
10 - 20 - occasional horizontal nystagmus
20 - 30 - nystagmus+
30 - 40 - ataxia, slurred speech, tremmors, NV
40 - 50 - lethargy, confusion and hyperactivity
> 50 mg/L. - Coma and seizures

IV phenytoin can have cardiac effects;
Rare side effect of IV phenytoin : purple glove syndrome: distal oedema of limbs with necrosis.

==Phenytoin worsens primary generalized epilepsies.==
📑Phenytoin worsens absence seizures and myoclonic seizures.

Management of phenytoin toxicity

Supportive; mortality rate is low.

Phenytoin side effects

• has narrow therapeutic window! (like lithium, digoxin, theophylline)
• #enzymeInducer - caution with OCP!
• Toxic Epidermal Necrolysis - Idiosyncratic!
• Gingival swelling (due to inflammation)
• Liver damage
• Teratogen
• contraindicated to control seizures caused by Na Channel blocking drugs - TCAs
• Antifolate drug -> can cause aplastic anaemia
• Hypertrichosis (Non androgen dependent hair growth)
• Motor neuropathy

Phenytoin Vs. Phenobarbitone

Phenytoin is structurally related to the barbiturates.

Antiepileptic drugs in pregnancy

• Valproate is particularly teratogenic. Very high in incidence of congenital defects.
  • therefore, used only as last line in women of child bearing age.

Anticonvulsant hypersensitivity syndrome

New name is DRESS. "Drug reaction with eosinophilia and systemic symptoms.".
Occurs between 2 - 8 weeks after starting the drug.
Can occur with many drugs, including antiepileptics.
Features:

• Fever
• Rash - maculopapular. Mucosal involvement can occur but much less than SJS.
• Facial oedema
• Lymphadenopathy
• Any other organ involvement
  • Commonest is liver
  • AKI, Heart, pulmonary

Management of status epilepticus

Rapid summary:

1. Airway, breathing, circulation stabilization
2. First dose of diazepam or lorazepam
3. If not responding, second dose after 5 minutes
4. Repeat a third dose of benzodiazepine.
5. If not responding at 15 minutes, emergency neurology consultation
   1. Start IV fosphenytoin 5-10 of PE/kg (PE - phenytoin equivalents)
      1. Forphenytoin is the less cardiotoxic prodrug of phenytoin.
      2. Calculate the required phenytoin dose.
      3. Administer that number of "phenytoin equivalents";
      4. Source
   2. Prepare for ICU transfer
6. If seizure continuing at 30 minutes, prepare for rapid sequence intubation and start midazolam infusion / propofol / phenobarbital.
7. Titrate infusion.
   See UpToDate algorithm for details.

Prostaglandin and COX pathway

A Good overview of arachidonic acid metabolism in the context of mechanism of action of paracetamol <- lots of detail; too long to read in a hurry.

COX = cyclooxygenase

PGHS = prostaglandin synthesae = cyclooxygenase

Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandin (PG) synthesis.
COX 1 = present in most tissues; "housekeeping". Protects the gastric mucosa, kidney function, platelet activation
COX 2 = usually expressed in brain, kidney and bone. During inflammation, it is expressed in other tissues as well.

The synthesized prostaglandins bind to G protein coupled receptors to exert their effects.

The graph shows the concentration of each drug needed to reduce activity of the COX 1 and 2 enzymes by 50% (IC50).

• Drugs below the diagonal line are COX 2 selective.
• Drugs toward the lower left are stronger inhibitors than ones at the upper right

COX and fever

Fever occurs due to the induction of COX-2 and subsequent increase in PGE2.
Recently a COX-3 isoform has been discovered. It was shown to be more sensitive to inhibition by paracetamol than other COXes and, so, was thought to be the target of analgesic and antipyretic effect of paracetamol; but this has been disproved.

NSAIDS

NSAIDs have

• anti-inflammatory action: reduced PGE2 -> reduced vasodilation
• Analgesic action: decreased prostaglandin -> reduced sensitizatin of nociceptors
• Antipyretic action: preventing synthesis of interleukin 1.

Most NSAIDS inhibit COX-1 by competitive reversible inhibition.
COX-2 inhibition is usually irreversible.

The antiplatelet action of aspirin isn't seen with other NSAIDS.
NSAIDS other than aspirin tend to have deleterious cardiovascular effects: they can cause hypertension by interfering with macula densa function.

Paracetamol is an NSAID-like drug with antipyretic and analgesic properties but no antiinflammatory properties.

NSAIDS and renal injury

Kidney PGs are primarily local vasodilators.
In the setting of hypotension and reduced kidney perfusion from vasoconstriction stimulated by angiotensin II, norepinephrine, vasopressin, or endothelin, PG synthesis is increased to maintain kidney perfusion and minimize ischemia
PGs also increase renin secretion, antagonize the water-retentive effects of arginine vasopressin, and enhance sodium excretion (See "NSAIDs: Electrolyte complications")
NSAIDS can cause hyperkalemia, hyponatremia and oedema

Hemodynamically mediated AKI due to NSAIDs occurs via attenuation of PG-mediated renal vasodilation. In healthy patients, PGs play little role in renal hemodynamics.

NSAID comparison

Source - Katzung

• All including aspirin, are equally efficacious.
  • Tolmemetin is best for gout.
• Ketorolac is known for renal and GI side effects.
• Indomethacin and tolmetin may be the most toxic.
• Least toxic: ibuprofen, aspirin.
• Diclofenac: more liver function test abnormalities than other NSAIDs.
• Ibuprofen antagonizes the antiplatelet effect of aspirin.
• COX-2 selectives has lower GI bleeding risk but higher cardiovascular risk.

Pharmacokinetics overview

[!INFO] Pharmacokinetics Vs. Pharmacodynamics
Dynamics = 'power'
Pharmacodynamics = effect drugs have on the body.
Pharmacokinetics = effect body has on drug concentrations.

Bioavailability

#2020BSQ-NOV/Q17

• The fraction of orally administered drug dose drug that reaches the circulation intact (i.e after the effects of first pass metabolism)
• Bioavailability of an IV drug is 1 by definition.
• In other words, bioavailablity is reduced both by decreased absorption and by breakdown by hepatic and intestinal enzymes. [[General Pharmacology#First pass metabolism]]

$$
Bioavailability=\frac{AUC_{oral}}{AUC_{IV}}
$$
where AUC = area under the curve for drug concentration Vs. time graph.
#2020BSQ-JUL/Q20

• Bioequivalence indicates that the drug products, when given to the same patient in the same dosage regimen, result in equivalent concentrations of drug in plasma and tissues.
• Therapeutic equivalence indicates that drug products, when given to the same patient in the same dosage regimen, have the same therapeutic and adverse effects.
• Bioequivalent drugs are generally expected to be therapeutically equivalent.

Calculating drug doses

Epic article by DeragedPhysiology
#2022BSQ Q17

Loading dose

Given when time-to-steady-state (4-5 half lives) would be too long to wait for the drug to take action.
$$Loading\space Dose = \frac{{Vd}\times{Tc}}{F}$$
Vd = volume of distribution, Tc = Target concentration, F = bioavailability

Dose rate and maintenance dose

For IV drugs given by infusion,

• Dose rate (mg/hr) = dose (mg) divided by dosing interval (hrs)
• Maintenance dose rate (mg/hr) = desired peak concentration (mg/L) × clearance (L/hr)
• Loading dose = desired peak concentration (mg/L) × volume of distribution (L)

For drugs not given IV, these doses need to be divided by the bioavailability.

Half life:

The equation describing the half life of a drug:
$$
\large{C_t = C_0exp\frac{-CL_{tot}}{V_d}t}
$$
where 'exp' means e to the power of'.

alternative form
$$
\large{C_t = C_0.e^{-kt}}
$$

The elimination constant

The exponent part in the equation above is the elimination rate constant.
CLtot = total clearance (i.e plasma volume which contains the amount of drug removed by all systems in a unit time)

$$
\frac{-CL_{tot}}{V_d} = \text{elimination rate constant} = k_{el}
$$

[!INFO] Half life depends on clearance and volume of distribution
$$
half\space life = \frac{0.693}{K_{el}}
$$

Therapeutic index

$$
\Large{Therapeutic\space Index=\frac{LD_{50}}{ED_{50}}}
$$
Higher therapeutic index => less toxic drug (high LD or low ED)
Lower therapeutic index => more toxic drug (low LD or high ED)

Effect of #pregnancy on pharmacokinetics

#2020BSQ-NOV/Q15

• There is increased plasma volume and total body water (and also increased body fat)
  • There is also decreased blood pressure [[Hypertension in pregnancy#Normal variation of blood pressure in pregnancy|normal variation in pregnancy]] (? what's the pharmacokinetic significance?)
• Maternal plasma albumin is reduced -> lower protein binding of drugs.
  • Drug + albumin <-> drug/albumin complex (low albumin = more unbound drug)
• Cardiac output is increased
• Therefore, GFR is increased and renal clearance of drugs is increased.
• Lipophillic drugs cross the placenta readily.
• The placenta prevents passage of drugs like enoxaparin
• Drugs that do cross the placenta are eliminated more slowly from the foetus.
• Foetal drug clearance is low because
  • Foetal liver enzymes are less active
  • Foetal urine is swallowed so drug isn't excreted.
• Delayed gastric emptying
• Generally, hepatic enzymes are induced. Source

Effect of liver failure on pharmacokinetics

Mathematics of hepatic pharmacokinetics

Source

[!INFO]
Extraction ratio : Hepatic extraction ratio ... is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
$$
\large Extraction\space Ratio = \frac{C_{arterial} - C_{venous}}{C_{arterial}}
$$
Protein binding affects hepatic extraction ratio because hepatocytes have access only to the unbound form of the drug.
Therefore, the equation above is equivalently represented as
$$
\large E_H = \frac{fu\times Cl_{int}}{Q_{H}+fu\times Cl_{int}}
$$

• (EH = hepatic extraction ratio)
• (Cl = intrinsic clearance)
  • Intrinsic clearance is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
  • It basically expresses how powerful the liver enzymes are at removing a drug.
• Fu - Fraction of unbound drug in the plasma
• QH - hepatic blood flow
  Finally we have the following equation for hepatic clearance: (ClH)
  $$
  \large Cl_{H} = Q_{H} \times \frac{fu\times Cl_{int}}{Q_{H}+fu\times Cl_{int}}
  $$
  So, we can see that hepatic clearance is affected by

1. Hepatic blood flow
2. Unbound fraction of the drug
3. Intrinsic ability of the liver to metabolize the drug

[!INFO] The upshot
Drugs with low intrinsic clearance will have "intrinsic limited" clearance
Drugs with high intrinsic clearance will have "flow limited" clearance.
Extraction ratio for all drugs decreases with increasing hepatic flow.

Effects in liver failure

In liver failure,

• There is increased body water -> volume of distribution is increased, lowering drug concentration.
• Hypoalbuminaemia / hypoproteinaemia -> lower protein -> higher concentration of highly protein bound drugs -> eg Aspirin, warfarin, phenytoin, benzodiazepines.
• Bilirubin can displace drugs from bound proteins -> increased Fu above. (?mild effect of increasing clearance)
• Intrinsic clearance will be reduced -> hepatic clearance is reduced -> higher drug concentrations.
• Hepatic blood flow is reduced due to
  • portosystemic shunting. [[2020-NOV-BasicSciences#Mechanism of porto-systemic shunting]] -> hepatic clearance is reduced.
  • Inotropes causing splanchnic vasoconstriction -> reduced hepatic blood flow.
  • Most drugs have low extraction ratios and clearance is dependent on intrinsic clearance capacity of the liver.

Chronic steroid use

Side effects

1. HPA Axis - glucocorticoids suppress CRH and ACTH.
2. Cushings

clinically desirable effects of steroids appear to result primarily from transrepression, which results in the decreased production of proinflammatory proteins

[!INFO] Glucocorticoids have non-genomic effects as well
"Nongenomic effects of glucocorticoids include rapid, nonspecific interactions of glucocorticoids with cellular membranes, nongenomic effects medicated by cytosolic glucocorticoid receptors, and specific interactions with membrane-bound glucocorticoid receptors"

[!INFO] Irriversible side effects
With the exception of cataracts, a potential acceleration in atherosclerotic vascular disease, and bone effects (osteoporosis and osteonecrosis), all glucocorticoid toxicity is at least partially reversible over time with glucocorticoid discontinuation

Other side effects of steroid

1. Cushingoid features - Redistrubition of fat, coupled with weight gain due to increased appetite.
2. Ophthalmologic effects - cataract (usually bilateral and distinct from age related cataract) and glaucoma and rarely exophtlamos
3. Cardiovascular
   1. Fluid retention and hypertension - particularly at high doses.
   2. In healthy individuals, fluid retention is counteracted by "aldosterone escape mechanism". ( #2020BSQ-NOV/Q06)

      Pathologic Increase in aldosterone can cause salt and water retention. But after a few days (or about 3Kg gain in weight), diuresis occurs. This is in response to

      1. increased ANP secretion
      2. Pressure natriuresis - kidney decreases Na resorption in response to increased perfusion pressure
      3. Decreased DCT resorption of Na via downregulation of thiazide sensitive sodium chloride co-transporter. ^c2b35e

   3. Increased rate of progression of atherosclerosis and increased risk of ACS and stroke
   4. Increased risk of AF and Atrial flutter
4. Gastric - ulcers, perforations, hepatic steatosis
5. Bone - osteoporosis and osteonecrosis [[Hormone Physiology#Regulation of bone formation and resorption]]
   1. Glucocorticoids increase resorption and decrease formation by binding to receptors in the bone cells.
   2. Gut absorption of calcium is reduced, and urine calcium loss is increased.
      1. Can cause a secondary hyperparathyroidism.
6. Myopathy - uncommon; painless proximal myopathy
7. Neuropsychiatrics - mood disorders, psychosis, memory impairement
8. Metabolic
   1. Hyperglycemia -
   2. including augmentation of hepatic gluconeogenesis, inhibition of glucose uptake in adipose tissue, and alteration of receptor and postreceptor functions
9. Immune - predisposition to infection
10. Haematologic - neutrophil leukocytosis <- decreased adhesion of neutrophils to the vessel walls. (?something to do with neutrophil rolling and adhesion in acute inflammation?)

Enzyme inducers and inhibitors

https://www.ncbi.nlm.nih.gov/books/NBK553990/table/ch31.Tab1/

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2044.2005.04462.x

Methotrexate

Antifolate drug;
Absolute contraindications: pregnancy, breast feeding, alcoholism and alcoholic liver disease, any other type of chronic liver disease, leukopenia / thrombocytopaenia, anaemia, bone marrow hypoplasia.

Antiepileptic medications

Mechanisms of action

For some drugs, precise mechanism is unknown or several mechanisms are suspected.

See table in up to date

Alteration of sodium currents is the most common mechanism of action of available antiseizure medications.

Type of receptor blockade may explain why some drugs are more effective for particular types of seizures.

Phenytoin , phenobarbitone and carbamazepine are some of the oldest antiseizure medications. - Newer drugs have better pharmacokinetics.

Carbamazepine

Binds Na Channels

This binding extends the inactivated phase and inhibits the generation of rapid action potentials when the cell is experiencing incoming depolarizing trains

#TODO

Phenytoin and fosphenytoin

#2023SBR Q23

Fosphenytoin is the prodrug. Superceded Phenytoin for IV use. (? Not really in SL)
Block Na channels, like carbamazepine.
Inhibits synaptic transmission.
And others...

seizure types

focal and generalized seizures
for status epilepticus
and as a second-line agent for patients with mixed seizures

Pharmacology of Phenytoin

95% protein bound ; renal failure impairs protein binding.
Valproate is another highly protein bound drug which ?may displace Phenytoin and increase its plasma levels.

potent, broad spectrum CYP and glucuronidation inducer.

Side effects:
Systemic: gingival hypertrophy, body hair increase, rash, folic acid depletion, reduced bone density (enzyme induction -> incr. Vitamin D catabolism)

Stevens-Johnson / TEN (commoner in south Asia!)

[!INFO] Ataxia
"ataxia" - disordered

Neurologic :
confusion
Slurred speech, ataxia, diplopia (all involving the head region)
Neuropathy

Phenobarbital / Phenobarbitone

• Different names for the same drug.
• Binds GABA-A receptor, potentiates GABA action, causing hyper polarization and increased neuronal stability.
• potent, broad spectrum CYP and glucuronidation inducer.
• Side effects:
  • Commonest side effect: sedation, reduced concentration, and mood changes including depression
  • Teratogenicity with #pregnancy is another risk, with a relatively high rate of major malformations in fetuses exposed to phenobarbital.
  • Chronic use is associated with an increased risk of decreased bone density, Dupuytren contractures, plantar fibromatosis, and frozen shoulder.

Enzyme inducers and inhibitors

[!TIP] left Side - Inhibitors; Right side - INDUCERS,

Protein bound drugs

The protein bound from and free form of drugs are in equilibrium. The bound form acts as a reservoir. The unbound form is active and also subject to elimination.

The free, unbound portion of a drug can be very small. (1%).
The most important protein which binds drugs is albumin.
Albumin binds many acidic drugs - warfarin, NSAIDS, Sulfonamides.
and fewer basic drugs (TCA, chlropromazine).

For most drugs at therapeutic concentration, the carrier proteins are very far from saturated.
At these concentrations, bound fraction does not changes with drug concentration.

However, tolbutamide almost completely saturates proteins at therapeutic level. So increasing dose increases the free proportion disproporionately. (Tolbultamide is a nonantimicrobial sulfonamide)

Sulfonamides have very high affinity so they occupy about 50% of the binding sites on albumin. This allows sulfonamides to significantly displace other protein bound drugs.

From DerangedPhysiology:

• Clinical significance of drug protein binding:
  • VOD: smaller for drugs with are highly plasma protein bound, larger for drugs which are highly tissue protein-bound
  • Metabolism and clearance: only the free fraction is usually available for dialysis, renal elimination and hepatic metabolism (with some exceptions)
  • Measured drug levels: total drug level may underrepresented clinically relevant concentration of free biologically active drug if there is hypoalbuminaemia
  • Displacement by other drugs, where there is competition for binding sites.

Selected drugs which are highly protein bound
Source

1. Phenytoin [[#Phenytoin toxicity]]
2. Warfarin
3. Levothyroxine
4. Ibuprofen, indomethacin,
5. Tolbutamid - contains a sulfa group
6. Acetazolamide
7. Amiodarone

Sulfonamides / sulphonamides

Initially developed as antibacterials; not used much now for that role (because of resistance) except for

1. sulfamethoxazole (given in combination with trimethoprim as co-trimoxazole, i.e TMP-SMX) -> Pneumocystis jirovecii infection, Stenorophomonas
2. Sulfasalazine (poor GI absorption - used for UC and crohn's)
3. Silver sulfadiazine

Non antibacterial sulfonamides

1. prasugrel
2. acetazolamide
3. Celecoxib and some other COX-2 inhibitors

There are antimicrobial and non antimicrobial sulfonamides: There's a large list!
List

Sulfonamide-containing nonantimicrobial agents (Table 1) include agents from therapeutic classifications such as thiazide and loop diuretics, carbonic anhydrase inhibitors, nonsteroidal anti-inflammatory drugs, sulfonylureas, antiretrovirals, and 5HT-3 receptor agonists

In the general population, approximately 3–8% of patients are reported to experience a sulfonamide allergy.
Stevens-Johnson syndrome can occur.

[!INFO] Allergy
Although many types of drugs have the NH2-SO2 sulpha group and are therefore technically 'sulfa-drugs', they don't have some additional group which are responsible for the allergies caused by the antibacterial sulphonamides. Therefore, cross reactivity and allergy risk is low.

The nonantimicrobial sulfonamides do not undergo metabolism to the N4-hydroxylated metabolite associated with SJS and will not bind to IgE at the N1 position and, therefore, are unlikely to cause cross-reactivity, even in patients who have experienced type 1 hypersensitivity or serious non-type-1 hypersensitivity reactions to sulfonamide antimicrobial agents.

Drugs Showing Zero order kinetics

#2020BSQ-JUL/Q19
📑 A few known drugs show zero order / 0 order kinetics.
==Most drugs show first order kinetics==.
ChatGPT: (verified)

1. 📑Aspirin - At high doses. Low doses -> first order.
2. Phenytoin
3. Ethanol
4. Salicylates other than aspirin (sodium salicylate)
5. 📑 Lithium
6. Procainamide
7. 📑 Omeprazole
8. 📑 fluoxetine
9. cisplatin

Important implications for saturation kinetics:

• Duration of action is more dependent on the dose.
• Plasma concentration is unpredictable

Illustration of the difference of variation in plasma concentration between zero and first order kinetics:

Phenytoin is the classical poster child for non-linear elimination kinetics, because the enzyme saturation point is reached somewhere in the middle of the therapeutic concentration range - Deranged Physiology

Efficacy and potency

#2018BSQ-OCT/Q02
Efficacy is the maximum effect that a drug can exert.
Potency is the concentration/dose of drug required to exert 50% of it's maximal effect.
Source

Efficacy:

A has higher efficacy than B.
But the dose at which 50% of maximum drug effect is achieved for Both A and B are similar. (?so similar potency?)

Therapeutic efficacy and pharmacological efficacy

The concept above is therapeutic efficacy.
Pharmacological efficay (also called Intrinsic efficacy) is

is the drug's maximal efficacy as a fraction of the maximal efficacy produced by a full agonist of the same type acting through the same receptors under the same conditions

Potency

A and B have the same maximum effect (i.e same efficacy) but A achieves this at a lower dose; Therefore, A is more potent.


Drug B is more potent than Drug A. Drug A and B have the same efficacy.
However, A has a steeper dose response curve so it requires a smaller increase in dose than B to achieve maximum effect.

Calcium channel blockers

#2022SBR-MAY Q08

[!TIP] Dihydropyridines end with 'pine'

Calcium channel blockers block the voltage gated L type calcium channels on cells, inhibiting calcium entry.
They show 'use dependence' so that they most affected tissues are heart and smooth muscle.

In smooth muscle, they cause relaxation -> predominant clinical effect is arteriolar dilation and coronary artery dilation; lowers blood pressure but also causes oedema.

In the heart, they have delay conduction and have a negative inotropic effect.

Site of action:
Most dihydropyridines affect smooth muscles more than the heart.
Ditiazem (nondihydropyridine) has intermediate action.
Verapamil acts mainly on the heart.

[!INFO] Specificity of heart Vs. smooth muscle lies along a spectrum

• CCBs acting on smooth muscle cause reflex tachycardia (and oedema).
• Diltiazem does not affect heart rate.
• Verapamil has negative chronotropic and inotropic effects.
• 
  Dihydropyridine structure kind of looks lika a smooth muscle cell.

Side effects are extensions of the pharmacological action.
Hyperglycemia is a side effect of CCB overdose which helps differentiate this from beta blocker overdose.

Toxic shock syndrome

#2022SBR-MAY Q14

Caused by TSST-1 toxin produced by staph aureus.
Toxin causes cytokine release which leads to rapid (48 hr) development of clinical features:

• Fever
• Hypotension
• Organ failure
• Macular rash
• Desquamation of palmar and plantar skin.
• Mucosal hyperaemia - vaginal and oropharyngeal mucosa. (can have bullae and vesicles)

Treatment:

1. Treat shock
2. Source control - i.e wound exploration
3. Antibiotics - antistaphylococcal antibiotic (carbapenem or penicillin + beta lactamase inhibitor) AND clindamycin to suppress toxin production.

Staphylococcal scalded skin syndrome

Occurs in children < 5 years old.
Exfoliatin produced by Staph aureus causes intrapidermal separation of the skin (at level of stratum corneum) resulting in flaccid blisters. Benign condition. Only requires flucloxacillin.

[!INFO] Mast cells

Henoch Schonlein purpura

Previously called IgA vasculitis.
Symptoms:

• Colickly abdominal pain
• followed by purpura on anakles -> elbows and lumbosacral area.

Diagnosis of active TB

• Chest X ray - Classic finding: upper lobe cavitation + bilateral hilar lymphadenopathy.
• Sputum smear: sensitivity = 50 - 80%.
• Sputum culture : Gold standard - the most sensitive test.
  • But takes 1 - 3 weeks.
• Nucleic acid amplification test - more sensitive than smear but less than culture. (takes 24-48 hours)
  • This is the Xpert MTB/RIF assay, a real time TB-PCR test.

We are concerned with the true positive rate and true negative rate of a test.

• true positive rate = sensitivity
• true negative rate = specificity

[!INFO] interpretation of sensitivity and specificity
SNOUT and SPINS

• Sn: Sensitive test rules out the disease when it is negative.
• Sp: specific test rules in a disease when it is positive.

Type 1 and type 2 errors

This part is intuitive:

• When a test is not sensitive, it has a high false negative rate. (Type 2 error)
• When a test is not specific, it has a high false positive rate. (Type 1 error)

[!INFO] Type 1 Vs type 2 error

• When the boy cried wolf for the first time and the villagers believed him : type 1 error
• When the boy cried wolf for the second time, the villagers didn't believe him : type 2 error.

[!INFO] prerequisite knowledge:

• What is parametric statistics?
• The branch of statistics which assumes that underlying population characteristic follows a known distribution which can be described with certain parameters. The most common such distribution is the normal distribution.
• But other distributions can also be assumed in parametric statistics. (The chi squared distribution, the poisson distrubition etc)
  [!WARNING] Wilcoxon rank sum test is the same as Mann-whitney U test
  Mnemonic: Both have U in the name

t-tests

Assumptions made with regards to independent samples t-tests

• There is theoretically no minimum sample size but the following must be satisfied.
• The dependent variable should be continuous (i.e ratio/interval)
• Independent variable should consist of two categorical groups
• independence of observations: No relationship between observations within or between groups.
  • Eg: no overlap of participants between the two groups
  • If this is not met, a paired sample t-test should be done.
• no significant outliers: outliers make the t-test less reliable.
• Dependent variable should be approximately normally distributed. Note: ordinal scales used in surveys don't yield normally distributed results.
  • Normalcy of data can be tested with the goodness-of-fit tests like the shapiro-wilk test.
• homogeneity of variances: The variances of data in both groups should be similar.
  Same as Wilcoxon rank sum test
  T-test assumptions: Source

Levels of measurement

Nominal = categorial
No sense of order.
Frequency or percentage is used to summarise.

Ordinal:
Have an order.
But the interval between values is unequal.

Interval / ratio
Things that can be measured

Power of a study

• The probability of not making a type 2 error
  Or equivalently
• the probability of rejecting the null hypothesis when it is false.

The probability that a study will detect a difference in measurement between two groups when such a difference actually exists, given a pre-set p alpha and sample size.

Metabolic alkalosis

Source

[!INFO] Pendrin
Is a key transport protein involved in pathogenesis.

"internal potassium balance".

The transcellular shifts in K+ caused by acid base changes.
Basis: In acidosis, about half the H+ is buffered intracellularly. To maintain electroneutrality, intracellular K+ moves outwards into the ECF.

[!INFO] Hypoaldosteronism
In patients with hypoaldosteronism, for example, the mild metabolic acidosis is primarily due to the associated hyperkalemia
UpToDate

Familiar mediterranean fever

• #autosomal-Recessive
• Episodes of fever with serositis lasting 1-3 days. (pleurisy, pericarditis, arthritis)
• more common in Turkish, Armenian and Arabic descent.
• Colcichine produces quick relief.